Relapses in giant cell arteritis: Updated review for clinical practice.

Giant cell arteritis (GCA), the most common primary vasculitis in adults, is a granulomatous systemic vasculitis usually affecting the aorta and its major branches, particularly the carotid and vertebral arteries. Although remission can be achieved in most patients with GCA using high-dose glucocorticoids (GC), relapses are frequent, occurring in >40% of GC-only treated patients, mostly during the first two years after diagnosis. Relapsing courses lead to high GC exposure, increasing the risk of treatment-related adverse effects. Although tocilizumab is an efficacious GC-sparing therapy that allows increased sustained remission and reduced cumulative GC doses, relapses are common after drug discontinuation. This narrative review examines the most relevant features of relapses in GCA, including its definition, classification, frequency, clinical, laboratory, and imaging characteristics, chronology, probable pathophysiology, and predictive factors. In addition, we discuss treatment options for relapsing patients and the effect of relapses on patient outcomes.

Inflammatory activity affects the accuracy of liver stiffness measurement by transient elastography but not by two-dimensional shear wave elastography in non-alcoholic fatty liver disease.

BACKGROUND: In patients with non-alcoholic fatty liver disease (NAFLD), the impact of the severity of steatosis and inflammatory activity on the accuracy of liver stiffness measurement (LSM) by transient elastography (TE) and by two-dimensional shear wave elastography (2D-SWE) in staging liver fibrosis is still debated and scarce. We aimed to focus on this aspect. METHODS: We prospectively studied 104 patients requiring biopsy for the assessment of NAFLD. We used ordinary least squares regression to test for differences in the association between fibrosis and LSM by TE and 2D-SWE when other factors (steatosis and inflammatory activity) are considered. RESULTS: Among 104 patients, 102 had reliable LSM by TE, and 88 had valid LSM by 2D-SWE. The association between fibrosis based on histology and LSM was significantly stronger when 2D-SWE assessed LSM compared to TE (Spearman's correlation coefficient of .71; P < .001 vs .51, P < .001; Z = 2.21, P = .027). Inflammatory activity was an independent predictor of LSM by TE but not of LSM by 2D-SWE. After controlling for fibrosis, age, sex and body mass index, the inflammatory activity and the interaction between inflammatory activity and fibrosis independently explained 11% and 13% of variance in LSM by TE respectively. Steatosis did not affect the association of fibrosis and LSM by either method. CONCLUSION: Inflammatory activity on histology significantly affects LSM by TE, but not LSM by 2D-SWE in NAFLD. LSM by 2D-SWE reflects liver fibrosis more accurately than LSM by TE. Furthermore, the severity of steatosis on histology did not influence the association of LSM and fibrosis by either elastography method.

Potent and Selective Activity against Human Immunodeficiency Virus 1 (HIV-1) of Thymelaea hirsuta Extracts.

Historically, natural products have been the most successful source of inspiration for the development of new drugs. Members of the Thymelaeaceae family have been of interest owing to their excellent medicinal value. Given the successful history of natural product-based drug discovery, extracts from the aerial parts of Thymelaea hirsuta were essvaluated for their potential anti-human immunodeficiency virus type 1 (HIV-1) activity. Ethyl acetate extracts from leaves (71B) and branches (72B) of Thymelaea hirsuta showed potent and selective activity against HIV-1 wt (EC50 = 0.8 µg/mL) at non-cytotoxic concentrations (CC50 > 100 µg/mL). They proved to be active against HIV-1 variants carrying clinically relevant NNRTI and NRTI mutations at low concentration (0.3-4 µg/mL range) and against the M-tropic strain HIV-1 BaL. The 72B extract, chosen as a lead, was not able to inhibit the RT and protease enzymatic functions. Furthermore, it was not virucidal, since exposure of HIV to high concentration did not affect virus infectivity. The pre-clinical safety profile of this extract showed no adverse effect on the growth of Lactobacilli, and non-toxic concentration of the extract did not influence the Caco-2 epithelial cells monolayer integrity. Additionally, extract 72B prevented syncytia formation at low concentration (0.4 µg/mL). The potent inhibitory effect on the syncytia formation in co-cultures showed that 72B inhibits an early event in the replication cycle of HIV. All of these findings prompt us to carry on new studies on Thymelaea hirsuta extracts.

Controlled attenuation parameter reflects steatosis in compensated advanced chronic liver disease.

BACKGROUND & AIMS: Controlled attenuation parameter (CAP) for steatosis assessment has not been validated in compensated advanced chronic liver disease compensated advanced chronic liver disease (cACLD). We primarily aimed at assessing the accuracy of CAP for the diagnosis and quantification of steatosis in cACLD. Secondary aim: to assess the validity of non-invasive criteria for cACLD according to liver stiffness measurement (LSM). METHODS: This is a single-centre retrospective study including patients with cACLD defined as LSM ≥10 kPa, CAP measurement and liver biopsy (reference standard for steatosis and fibrosis) observed in 06/2015-06/2017. Steatosis was graded as S0 (<5%), S1 (5%-32%), S2 (33%-66%) and S3 (>66%). The diagnostic performance of CAP for any grade of steatosis and for high-grade steatosis (≥S2) was studied. RESULTS: Among 461 consecutive patients, 111 with LSM-based diagnosis of cACLD were included (63% male, median age 55 years, median body mass index 28.1 Kg/m2 , aetiology: 32% non-alcoholic fatty liver disease/non-alcoholic steatohepatitis, 32% alcohol or viral + metabolic syndrome, 15% viral, 6% autoimmune, 4% alcohol, 11% others). Median LSM and CAP were 16.1 kPa and 277 dB/m respectively. On liver biopsy, steatosis was found in 88/111 patients (79%); 44 patients (43 with metabolic syndrome) had high-grade steatosis. CAP was accurate in identifying any grade of steatosis (area under the receiving operating characteristic curves 0.847; 95% CI 0.767-0.926, P < .0001), and ≥S2 steatosis (0.860; 95% CI 0.788-0.932, P < .0001). CAP performed similarly in patients with CAP- interquartile range (IQR) ≥ or <40 dB/m. CONCLUSIONS: Steatosis is frequent in patients with cACLD and metabolic syndrome. CAP diagnostic accuracy for any steatosis and high-grade steatosis is good in this population. A CAP-IQR ≥40 dB/m does not impair CAP diagnostic accuracy in cACLD.

Description and Validation of Histological Patterns and Proposal of a Dynamic Model of Inflammatory Infiltration in Giant-cell Arteritis.

The extent of inflammatory infiltrates in arteries from patients with giant-cell arteritis (GCA) have been described using different terms and definitions. Studies investigating the relationship between GCA histological features and clinical manifestations have produced controversial results. The aims of this study were to characterize and validate histological patterns in temporal artery biopsies (TABs) from GCA patients, to explore additional histological features, including the coexistence of different patterns, and also to investigate the relationship of the inflammatory patterns with clinical and laboratory features.We performed histological examination of TAB from patients with GCA consecutively diagnosed between 1992 and 2012. Patterns of inflammation were defined according to the extent and distribution of inflammatory infiltrates within the artery. Clinical and laboratory variables were recorded. Two external investigators underwent a focused, one-day training session and then independently scored 77 cases. Quadratic-weighted kappa was calculated.TAB from 285 patients (200 female/85 male) were evaluated. Four histological inflammatory patterns were distinguished: 1 - adventitial (n = 16); 2 - adventitial invasive: adventitial involvement with some extension to the muscular layer (n = 21); 3 - concentric bilayer: adventitial and intimal involvement with media layer preservation (n = 52); and 4 - panarteritic (n = 196). Skip lesions were observed in 10% and coexistence of various patterns in 43%. Raw agreement of each external scorer with the gold-standard was 82% and 77% (55% and 46% agreement expected from chance); kappa = 0.82 (95% confidence interval [CI] 0.70-0.95) and 0.79 (95% CI 0.68-0.91). Although abnormalities on temporal artery palpation and the presence of jaw claudication and scalp tenderness tended to occur more frequently in patients with arteries depicting more extensive inflammation, no statistically significant correlations were found between histological patterns and clinical features or laboratory findings.In conclusion, we have described and validated 4 histological patterns. The presence of different coexisting patterns likely reflects sequential steps in the progression of inflammation and injury. No clear relationship was found between these patterns and clinical or laboratory findings. However, several cranial manifestations tended to occur more often in patients with temporal arteries exhibiting panarteritic inflammation. This validated score system may be useful to standardize stratification of histological severity for immunopathology biomarker studies or correlation with imaging.

Effect of glucocorticoid treatment on computed tomography angiography detected large-vessel inflammation in giant-cell arteritis. A prospective, longitudinal study.

Computed tomography angiography (CTA) detects signs of large-vessel vasculitis (LVV) in about 67.5% of patients with giant-cell arteritis (GCA) at the time of diagnosis and early aortic dilatation in 15%. The outcome of CTA-findings of LVV upon glucocorticoid treatment has not been prospectively evaluated. The aim of our study was to prospectively assess glucocorticoid-induced changes in CTA findings of LVV in patients with GCA. Forty biopsy-proven GCA patients evaluated by CTA at diagnosis were prospectively followed and scheduled a new CTA approximately after 1 year of treatment. Vessel wall thickening, diameter, and contrast enhancement of the aorta and its tributaries were evaluated. Results were compared to those obtained at the time of diagnosis. CTA was repeated to 35 patients after a median follow-up of 13.5 months (IQ25-75% 12.4-15.8). Arterial wall thickening was still present in 17 patients (68% of the patients who initially had LVV). The number of affected segments and wall thickness at various aortic segments significantly decreased and no patients developed new lesions, new aortic dilation or increase in previous dilation. Contrast enhancement disappeared in 15 (93.75%) of 16 patients in whom this finding could be assessed. Signs of LVV improve with treatment. While contrast enhancement resolves in the majority of patients, vessel wall thickening persists in two thirds. However, the number of affected aortic segments as well as aortic wall thickness significantly decreases. Longer follow-up is necessary to determine the clinical significance of persisting wall thickening and its relationship with relapses or subsequent development of aortic dilatation or large-vessel stenoses.

The salivary proteome profile in patients affected by SAPHO syndrome characterized by a top-down RP-HPLC-ESI-MS platform.

SAPHO syndrome is a rare and often unrecognized disease with prominent inflammatory cutaneous and articular symptoms characterized by musculoskeletal manifestations (synovitis, hyperostosis, osteomyelitis) associated with dermatological conditions (severe acne and pustulosis). The acidic soluble fraction of whole saliva from 10 adult women affected by SAPHO syndrome and from a group of 28 healthy women was analysed by RP-HPLC-ESI-MS with the aim of discovering salivary biomarkers of the disorder. The levels of the oral proteins and peptides were correlated with clinical data. The following proteins showed a significant decreased concentration in saliva of SAPHO subjects with respect to controls: cystatin S1 and SN, histatins, the major acidic PRPs, P-C and P-B peptides. The cystatin SN abundance lowered according to the disease duration and histatins showed positive correlations with the C reactive protein. Statistical analysis performed excluding one patient with a different pattern of salivary proteins/peptides highlighted a positive relationship between cystatin S1, histatins 3, histatin 5, and the neutrophil count. Moreover, histatin 3 correlated positively with the total white cell count and negatively with the erythrocyte sedimentation rate. Levels and frequency of S100A12 protein showed a trend to increase in SAPHO patients. The high expression of this pro-inflammatory protein is probably related to the inflammatory response and to the altered neutrophil responses to functional stimuli that characterize SAPHO syndrome suggesting a possible application as a salivary biomarker.

Biologics for ANCA-associated vasculitis.

The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a group of necrotizing vasculitides with a potential fatal outcome. Conventional therapy is based on the use of glucocorticoids (GCs) and cyclophosphamide (CYC), which is associated with severe toxic effects and is unable to control the disease activity in some refractory and relapsing cases. Several authors focused their efforts on the identification of safe and more efficient drugs, primarily investigating biological agents. Rituximab (RTX) demonstrated to be an alternative to CYC as remission-induction therapy for microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) in two clinical controlled randomized trials. Contrasting data emerged regarding anti-TNF-α agents, and their use should be limited to some selected refractory or relapsing cases. Mepolizumab (MPZ) and Omalizumab (OMZ) are potentially beneficial treatments for patients with eosinophilic granulomatosis with polyangiitis (EGPA). Hereby, we perform a review focused on the use of biological drugs for AAV treatment.

Biological treatments for SAPHO syndrome: an update.

Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis (SAPHO) syndrome is a rare and often unrecognized disease with prominent inflammatory cutaneous and articular manifestations. Since the identification of the syndrome many immunosuppressive drugs have been used for the management of SAPHO, with variable results. The use of anti- TNF-α agents as a therapeutic option for SAPHO cases unresponsive or refractory to conventional drugs, demonstrated their efficacy for bone, skin and joints manifestations. TNF-α is a pro-inflammatory cytokine and pivotal regulator of other cytokines, including IL-1 ß , IL-6 and IL-8, involved in inflammation, acute-phase response induction and chemotaxis. IL-1 inhibition strategies with Anakinra have proven their efficacy as first and second line treatment. We herein review the literature concerning the use of biological drugs in patients with SAPHO syndrome. In addition, we describe for the first time the use of Ustekinumab, an antibody against the p40 subunit of IL-12 and IL-23, after failure of multiple drugs including anti-TNF-α and Anakinra. This anti-IL12/IL23 agent could be a promising therapeutic option, also considering the opportunity to interfere with the IL23/TH17 pathway, which we recently found disturbed. Furthermore, a rationale emerges for the use of the new anti-IL-1 antagonists or the IL-17 blockade, in particular for the most difficult-to-treat SAPHO cases.